Cisplatin is a metallo anticancer drug which stops replication within cells by binding irreversibly to nitrogen (N7), of guanine (G) and adenine (A), and forming intrastrand and interstrand cross-links in the major groove of DNA. However, cisplatin binds indiscriminately and also binds with macromolecules other than DNA. This indiscriminate binding can lead to adverse effects in healthy cells. Cisplatin is currently used to treat a range of cancers including testicular, ovarian, bladder, head and neck, lung and cervical cancers. However, a drawback of cisplatin is that many human cancer cell lines have a natural resistance to cisplatin, and those that can be treated may later develop resistance to the drug. In addition, treatment with cisplatin may produce severe side effects in patients, including nephrotoxicity, neurotoxicity, ototoxicity, impairment of sex hormone production and psychosexual difficulties as well as nausea and hair loss. Second generation platinum drugs (such as carboplatin, ZD0473, oxaliplatin) have been developed, however, like cisplatin, they can cause indiscriminate, irreversible damage and disadvantageously may have similar negative side effect profiles.
Farrell, et al, Inorg Chem., 38, (1999), 3535 describe metallodrugs based on cisplatin but having two or three platinum centres linked by an alkyl chain. These compounds have been shown to cross the cell membrane and bind to DNA and are active in some cisplatin resistant cell lines. However, like cisplatin, these compounds are not sequence specific.
Brabec and co-workers (Biochemistry, 2000, 39, 12639-12649; Eur. J. Biochem. 1999, 266) have prepared compounds in which cisplatin is attached to the minor groove binding molecule, distamycin. However, whilst distamycin has an affinity for sequences in the minor groove, it is not sequence selective. Moreover, in those compounds the coupling of the platinum moiety to the very end of the distamycin restricts the binding interaction of both groups and neither the distamycin nor the platinum are in a position to optimise their binding interaction.
The present invention relates to compounds in which a metallo complex, such as a metallodrug or metallo-diagnostic compound, is attached to a sequence selective polyamide(s) as a means of selectively targeting the metallo complex to a particular sequence of interest.